This amended application seeks support for new work aimed at the treatment of vascular aging in humans. The proposed research will determine if habitual aerobic exercise improves endothelium-dependent dilation (EDD), a clinically important marker of vascular endothelial function and cardiovascular disease risk, in middle- aged/older adults by reducing tonic inflammation- and oxidative stress-mediated suppression of EDD. The proposed work also will provide novel insight into the cellular and molecular mechanisms by which regular aerobic exercise may improve tonic inflammation- and oxidative stress-mediated suppression of EDD. Integrative Working Hypothesis: In previously sedentary healthy middle-aged/older (60-79 years) men and women, the improvements in EDD in response to habitual aerobic exercise will be associated with reduced tonic inflammation-mediated suppression of EDD. The latter will, in turn, be related to: 7 a reduced systemic pro-inflammatory "milieu", characterized by decreased pro-inflammatory/increased anti-inflammatory plasma concentrations of cytokines and other inflammatory mediators 7 a reduced inflammatory vascular endothelial phenotype, characterized by decreased pro-inflammatory/ increased anti-inflammatory cytokine protein expression in the vascular endothelium 7 reduced vascular endothelial activation of the key inflammatory transcription factor, nuclear factor : B (NF:B), associated with changes in the proteins controlling its activation and nuclear translocation. The reduced tonic inflammation-related suppression of EDD will be associated with decreased oxidative stress-mediated inhibition of EDD. The latter will, in turn, be related to: 7 reduced systemic oxidative stress 7 a less pro-oxidant vascular endothelial phenotype, characterized in part by decreased oxidant enzyme and oxidation-modified protein expression in the vascular endothelium. Experimental Approach: We will conduct a 12-week aerobic exercise intervention (randomized design with attention control). The tonic influence of inflammation on EDD will be determined before and after the intervention period by the improvement in EDD in response to short-term blockade of NF:B signaling with orally administered Salsalate. The effects of oxidative stress will be assessed by the increase in EDD in response to acute administration of ascorbic acid (vitamin C), a potent antioxidant. Key outcomes will include brachial artery flow-mediated dilation (EDD) and measures of systemic and/or vascular endothelial inflammation, NF:B-related proteins, oxidative stress, and oxidant and antioxidant enzymes. PUBLIC HEALTH RELEVANCE: This application seeks support for new research aimed at the treatment of aging of the arteries in adults. The proposed research will determine if regular aerobic exercise improves the function of the arteries in middle- aged/older men and women and, if so, if a reduction in the state of inflammation is a major reason for the beneficial effects of exercise.